Edited by: Longxiang Su, Peking Union Medical College Hospital (CAMS), China
Reviewed by: Jianjun Ren, Sichuan University, China; Muneeb A. Faiq, New York University, United States
This article was submitted to Infectious Diseases – Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine
†These authors have contributed equally to this work and share first authorship
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease 2019 (COVID-19). COVID-19 has rapidly spread globally, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020. The mortality rate based on cumulative data is around 3.4% in China and 0.4% outside of China (
Spironolactone is used primarily to treat heart failure, edematous conditions such as ascites in severe liver diseases, secondary hyperaldosteronism due to liver cirrhosis, and essential hypertension (
In light of this theory, we have conducted a nationwide case-control study investigating whether spironolactone exposure could be associated with SARS-CoV-2's infectivity and complication rate in COVID-19 patients with liver cirrhosis. The null hypothesis was that there are no differences between patients with or without spironolactone exposure in terms of SARS-CoV-2's infectivity and complication rate of COVID-19.
This study was approved by the Institutional Review Board of Asan Medical Center (IRB number: 2020-1153) and written informed consent was waived by the board due to the de-identified nature of the data. The anonymized data obtained from the National Health Insurance claims of Republic of Korea were analyzed. The flow of the population in this case-control study is represented in
Study flow diagram.
In detail, the population-based dataset comprised all patients tested for COVID-19 from January 20, 2020, when the first case of COVID-19 was observed in South Korea, to May 15, 2020, including suspected and confirmed cases, with demographic information and medical services history for the past 3 years. The analysis was performed on 234,427 patients tested for COVID-19 with the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis codes of B342, B972, Z208, Z290, U18, U181, Z038, Z115, U071, and U072. Screening was conducted by performing polymerase chain reaction amplification of the viral E gene and the RdRp region of the ORF1b gene was amplified to confirm COVID-19. Among the total 234,427 patients with COVID-19 screening test results, 6,462 subjects were confirmed to have liver cirrhosis over 19 years. The presence of liver cirrhosis was established based on ICD-10 codes for liver cirrhosis (K702, K703, K704, K717, K720, K721, K729, K740-K746, K761, K766-K767, R18, I850, I859, I864, I868, I982, I983) (
Further subgroup analysis for complication rate was done on the case group. Complications due to severe COVID-19 disease were defined as cases requiring intervention, such as oxygen therapy, anti-viral therapy, vasopressors, admission to the intensive care unit, continuous renal replacement therapy, or death (
Exposure to spironolactone was defined as the administration of spironolactone at least once within 1 year before the date of COVID-19 testing. Two additional sensitivity analyses were performed to verify the robustness of the study findings. With at least one claim within 6 months and 3 months for prescription of spironolactone, we classified these according to exposure to spironolactone and performed additional analyses. In addition, to quantify the exposure to spironolactone and to determine the dose-response association, the cumulative defined daily dose (cDDD) of spironolactone during the exposure period was calculated (≤30 cDDD or >30 cDDD) (
Underlying diseases were established based on diagnosis codes of the ICD-10. The considered comorbidities were decompensated liver cirrhosis, diabetes, hypertension, dyslipidemia, cardiovascular disease including myocardial infarction and stroke, cancer, lung disease including chronic obstructive pulmonary disease and asthma, end-stage renal disease (ESRD) with dialysis, and immunocompromised status including autoimmune diseases and human immunodeficiency virus infections. These comorbidities in the present study were chosen based on the announcement of Centers for Disease Control and Prevention in the U.S that these comorbidities increased risk of severe illness from COVID-19 infection (
Baseline characteristics of case and control groups were presented as mean with standard deviation for continuous variables, and the number with percentage (%) for categorical variables. Comparisons between both groups were performed using Student's
Before matching, the number of patients in the case and control groups were 67 and 6,395, respectively. After matching, a total of 399 subjects were analyzed. The baseline characteristics of the study population are presented in
Baseline characteristics of patients with liver cirrhosis, according to COVID-19.
Sex, male, n (%) | 40 (59.7) | 197 (59.3) | 1.00 |
Age (years), mean (SD) | 59.9 (15.7) | 60.3 (15.3) | 0.85 |
Daegu and Gyeongbuk, n (%) | 43 (64.2) | 212 (63.9) | 1.00 |
Tertiary hospital, n (%) | 9 (13.4) | 45 (13.6) | 0.98 |
Decompensated liver cirrhosis, n (%) | 19 (28.4) | 154 (46.4) | 0.01 |
Diabetes, n (%) | 21 (31.3) | 121 (36.5) | 0.43 |
Hypertension, n (%) | 27 (40.3) | 185 (55.7) | 0.02 |
Dyslipidemia, n (%) | 19 (28.4) | 127 (38.3) | 0.13 |
Cardiovascular disease, n (%) | 9 (13.4) | 82 (24.7) | 0.04 |
Cancer, n (%) | 12 (17.9) | 113 (34.0) | 0.01 |
Lung disease, n (%) | 17 (25.4) | 120 (36.1) | 0.09 |
ESRD with dialysis, n (%) | 0 (0) | 21 (6.3) | 0.03 |
Immunocompromised status, n (%) | 9 (13.4) | 31 (9.3) | 0.31 |
Charlson Comorbidity Index, mean (SD) | 4.3 (2.7) | 6.3 (3.8) | <0.0001 |
35 (52.2) | 55 (16.6) | <0.0001 | |
Oxygen therapy, n (%) | 12 (17.9) | 32 (9.6) | 0.04 |
Antiviral therapy, n (%) | 28 (41.8) | 1 (0.3) | <0.0001 |
Vasopressors, n (%) | 4 (6.0) | 14 (4.2) | 0.52 |
Admission to the intensive care unit, n (%) | 2 (3.0) | 9 (2.7) | 1.00 |
Continuous renal replacement therapy, n (%) | 1 (1.5) | 1 (0.3) | 0.31 |
Death, n (%) | 6 (9.0) | 32 (9.6) | 0.86 |
7 (10.5) | 111 (33.4) | 0.0002 | |
Non-user | 60 (89.5) | 221 (66.5) | 0.0008 |
cDDD ≤30 | 3 (4.5) | 51 (15.4) | |
cDDD >30 | 4 (6.0) | 60 (18.1) |
The results of the logistic regression analysis for COVID-19 infection according to exposure to spironolactone are shown in
Odds ratios and 95% confidence intervals for COVID-19 according to exposure to spironolactone.
Total | 67 (100) | 332 (100) | ||||||
Without exposure to spironolactone | 60 (89.5) | 221 (66.6) | 1.00 | 1.00 | 1.00 | |||
Exposure to Spironolactone | 7 (10.5) | 111 (33.4) | 0.19 (0.08–0.47) | 0.0003 | 0.21 (0.08–0.55) | 0.001 | 0.20 (0.07–0.54) | 0.002 |
Non-user | 60 (89.5) | 221 (66.5) | 1.00 | 1.00 | 1.00 | |||
cDDD ≤30 | 3 (4.5) | 51 (15.4) | 0.22 (0.07–0.72) | 0.01 | 0.25 (0.08–0.86) | 0.03 | 0.23 (0.07–0.78) | 0.02 |
cDDD >30 | 4 (6.0) | 60 (18.1) | 0.25 (0.09–0.70) | 0.009 | 0.32 (0.11–0.93) | 0.04 | 0.30 (0.10–0.89) | 0.03 |
Total | 58 (100) | 287 (100) | ||||||
Without exposure to Spironolactone | 52 (89.7) | 187 (65.2) | 1.00 | 1.00 | 1.00 | |||
Exposure to Spironolactone | 6 (10.3) | 100 (34.8) | 0.17 (0.06–0.45) | 0.0004 | 0.198 (0.071–0.555) | 0.002 | 0.17 (0.06–0.49) | 0.001 |
Non-user | 52 (89.6) | 187 (65.1) | 1.00 | 1.00 | 1.00 | |||
cDDD ≤30 | 3 (5.2) | 51 (17.8) | 0.21 (0.06–0.71) | 0.01 | 0.26 (0.07–0.88) | 0.03 | 0.25 (0.07–0.87) | 0.03 |
cDDD >30 | 3 (5.2) | 49 (17.1) | 0.22 (0.07–0.74) | 0.01 | 0.27 (0.08–0.92) | 0.04 | 0.27 (0.08–0.93) | 0.04 |
Total | 49 (100) | 245 (100) | ||||||
Without exposure to Spironolactone | 43 (87.8) | 156 (63.7) | 1.00 | 1.00 | 1.00 | |||
Exposure to Spironolactone | 6 (12.2) | 89 (36.3) | 0.22 (0.09–0.56) | 0.002 | 0.26 (0.10–0.68) | 0.006 | 0.23 (0.08–0.64) | 0.005 |
Non-user | 43 (87.8) | 156 (63.7) | 1.00 | 1.00 | 1.00 | |||
cDDD ≤30 | 3 (6.1) | 48 (19.6) | 0.23 (0.07–0.76) | 0.02 | 0.25 (0.07–0.86) | 0.03 | 0.26 (0.08–0.90) | 0.03 |
cDDD >30 | 3 (6.1) | 41 (16.7) | 0.27 (0.08–0.90) | 0.03 | 0.31 (0.09–1.05) | 0.06 | 0.28 (0.08–1.00) | 0.05 |
For risk stratification, subgroup analyses for COVID-19 status were performed by stratifying the study population by sex and age. The results of these analyses are shown in
Baseline characteristics of the complication and no complication groups of patients with liver cirrhosis and COVID-19 infection are shown in
Baseline characteristics of patients with liver cirrhosis and COVID-19.
Sex, male, n (%) | 21 (60.0) | 19 (59.4) | 0.96 |
Age (years), mean (SD) | 63.5 (15.8) | 56.0 (14.8) | 0.05 |
Daegu and Gyeongbuk, n (%) | 21 (60.0) | 22 (68.8) | 0.46 |
Tertiary hospital, n (%) | 5 (14.3) | 4 (12.5) | 1.00 |
Decompensated liver cirrhosis, n (%) | 13 (37.1) | 6 (18.8) | 0.10 |
Diabetes, n (%) | 15 (42.9) | 6 (18.8) | 0.03 |
Hypertension, n (%) | 19 (54.3) | 8 (25.0) | 0.01 |
Dyslipidemia, n (%) | 9 (25.7) | 10 (31.3) | 0.62 |
Cardiovascular disease, n (%) | 4 (11.4) | 5 (15.6) | 0.73 |
Cancer, n (%) | 10 (28.6) | 2 (6.3) | 0.02 |
Lung disease, n (%) | 10 (28.6) | 7 (21.9) | 0.53 |
ESRD with dialysis, n (%) | 0 (0) | 0 (0) | - |
Immunocompromised status, n (%) | 4 (11.4) | 5 (15.6) | 0.73 |
Charlson Comorbidity Index, mean (SD) | 5.0 (2.9) | 3.5 (2.3) | 0.02 |
Oxygen therapy, n (%) | 12 (17.9) | – | – |
Antiviral therapy, n (%) | 28 (41.8) | – | – |
Vasopressors, n (%) | 4 (6.0) | – | – |
Admission for intensive care unit, n (%) | 2 (3.0) | – | – |
Continuous renal replacement therapy, n (%) | 1 (1.5) | – | – |
Death, n (%) | 6 (9.0) | – | – |
5 (14.3) | 2 (6.3) | 0.43 | |
Non-user | 30 (85.7) | 30 (90.9) | 0.12 |
cDDD ≤30 | 1 (2.9) | 2 (9.1) | |
cDDD >30 | 4 (11.4) | 0 (0) |
To summarize, the results showed that a significantly low proportion of cirrhosis patients with COVID-19 had previous exposure to spironolactone. Spironolactone was not significantly associated with complications. The factors associated with complications in cirrhotic patients with COVID-19 were diabetes, hypertension, cancer, and CCI score. This result of high-risk factors coincides with those indicated in previous studies (
The value of our study is that it provides theoretical evidence for the role of spironolactone in terms of COVID-19 susceptibility. A previous study by Cadegiani et al. (
In our study, the result showed that there were no statistically significant correlations between complication rate and spironolactone exposure. This result could be distorted because there were only 35 patients in the complication group, which were too small, and comorbidities were unequally distributed, specifically the significantly higher CCI score of the complication group compared with the no complication group, which could raise the complication rate. When baseline characteristics from previous studies were analyzed (diabetes, hypertension, cancer, and CCI) as risk factors for COVID-19 complications, they were higher in patients in the complication group compared with those in the without complication group (
We acknowledge the limitations of our study. First, we used data from national health insurance claims, which potentially caused some discrepancies between actual therapeutic practices. In addition, due to the nature of the present study, biases from the unequal distribution of comorbidities between the two groups might have affected the association between the use of spironolactone and COVID-19, despite statistical adjustments. Second, it was challenging to define ARDS, so complications induced by this condition included cases treated with oxygen therapy and other severe complications related to the disease. Third, the susceptibility of contagious diseases can be affected by multiple factors such as sociocultural factors, which can be difficult to anticipate. We were also not able to gather information regarding patients' lifestyle-related factors such as smoking and alcohol drinking, which might affect the outcome of our study. Additionally, there was a small number of COVID-19 cases in patients with liver cirrhosis. Moreover, our study lacked detailed information about severity or stage of liver cirrhosis. Therefore, our results should be interpreted with caution because only complications in patients with COVID-19 and liver cirrhosis, and whether these patients were exposed to spironolactone, were investigated. Our results should therefore be validated in a larger cohort study.
Our study is the first to investigate the impact of spironolactone on patient susceptibility to COVID-19, and the prevalence of its associated complications. Based on relevant statistical analysis, patients who were infected by COVID-19 with underlying liver cirrhosis showed significantly lower spironolactone exposure rate compared to patients who were not infected by COVID-19 with underlying liver cirrhosis. Therefore, our results suggested that exposure of spironolactone may reduce susceptibility to COVID-19 in patients with liver cirrhosis. Further studies are needed to confirm the exact association between spironolactone and COVID-19.
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at:
The studies involving human participants were reviewed and approved by Institutional Review Board of Asan Medical Center, Seoul, Republic of Korea (IRB number: 2020-1153). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
DJ, MS, and JC were responsible for the conception and design of the study, acquisition, analysis and interpretation of the data, and drafting of the manuscript. MS performed the statistical analyses. All authors have full access to all data used in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, and approved the final version of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank the Ministry of Health and Welfare, the Health Insurance Review and Assessment Service, and Yu Jin Lee of the Health Insurance Review and Assessment Service of South Korea for sharing invaluable national health insurance claims data and running the SAS code in a prompt manner.
The Supplementary Material for this article can be found online at:
Acute respiratory distress syndrome
Charlson Comorbidity Index
Confidence interval
End-stage renal disease
Odds ratio
Renin-angiotensin-aldosterone system
Defined daily dose
Severe acute respiratory syndrome coronavirus-2.